Method of treating hyperpigmentation



United States Patent O 3,517,105 METHOD OF TREATING HYPERPIGMENTATION John J. Miskel, East Orange, Edward R. Neary, Teaneck, and Walter Schlesinger, Westfield, N.J., assignors to Schering Corporation, Bloomfield, N.J., a corporation of New Jersey No Drawing. Filed Apr. 6, 1966, Ser. No. 540,501 Int. Cl. A611: 27/00 U.S. Cl. 424-315 5 Claims ABSTRACT OF THE DISCLOSURE A method of treating hyperpigmentation comprises applying topically to a hyperpigmented area a pharmaceutical formulation comprising from 0.1 to about 10.0% by weight of a member selected from the group consisting of p-aminobenzene-sulfonic acid and the alkali metal and alkaline earth metal salts thereof. Specifically described are pharmaceutical formulations comprising as depigmenting agent p-aminobenzene-sulfonic acid or the sodium or potassium salt thereof.

This invention relates to compositions of matter useful as depigmenting agents and to processes for utilizing such compositions in the treatment and control of hyperpigmentation.

Broadly, depigmenting agents are materials which are capable of reducing the melanin density of the melanocytes of the skin thereby producing a lightening in color of the integument. Although it is generally believed that the number of melanocytes in the skin does not vary substantially from individual to individual, melanin density and distribution within the melanocytes varies widely among individuals. Further, and of particular interest from the standpoint of the instant invention, there frequently occurs in a given individual a localized area of the skin wherein the melanin density within the melanocytes is markedly increased, resulting in a skin color in the area affected far darker than the normal background color. These localized areas of hyperpigmentation may be associated with a number of causative factors among which may be included inflammatory or traumatic lesions of the skin; genetic or racial characteristics, e.g. freckling, aging, systemic endocrine disease or exposure factors frequently characterized as chloasma, chloasma bronzium, chloasma phthisicum, chloasma uterinum, idiopathic chloasma and symptomatic chloasma, the area of hyperpigmentation persisting for extended periods even after correction of the underlying causal condition. The resulting disfigurement, which may be more or less permanent in character, is often a source of acute distress to the individual. In its milde'st form this type of hyperpigmentation is aptly described as resulting in a muddy complexion. It is contemplated that the depigmenting compositions of this invention will be applied topically in the treatment and control of such hyperpigmentation. It is also within the scope of this invention to correct the cosmetic disfigurement characteristic of areas of depigmentation as seen in vitiligo and leukoderma where the compositions of this invention will reduce the pigment in the normal area to blend with the areas devoid of pigment. The compositions will also reduce overall melanin density in normal skin as a function of the degree of melanin density in the melanocytes.

The compounds that have been employed previously in effecting depigmentation have been limited in number and, as a group, display serious drawbacks. of such compounds, the one most frequently used in dermatologic practice has been benzyloxyphenol, the monobenzyl ether of hydraquinone. The depigmentation activity of this com- Patented June 23, 1970 pound was uncovered in the early 1940s during an investigation of industrial dermatitis that occurred in the tanning industry. The leukoderma that was observed in Negro workers was traced to the use of benzyloxyphenol as an antioxidant in the protective rubber gloves worn by the workers. The observation led to extensive investigation of the mechanism and clinical use of this compound. It has been observed that benzyloxyphenol, a highly insoluble compound, apparently is not metabolized to any great degree when absorbed into the skin. For this reason, its use has been associated with frequent incidents of irreversible depigmentation simulating vitiligo. Further, clinical studies have indicated that apart from local irreversible depigmentation, the compound is transported by the lymph system and may cause irreversible depigmentation in areas of the body far removed from the site of the application. Methoxyphenol has also been reported to display depigmentation activity. This compound, however, like benzyloxyphenol, has a relatively high insolubility and is unable to be metabolized readily.

In addition, hydroquinone itself has been used extensively primarily in cosmetics, for the treatment of hyperpigmentation. While this compound is very soluble and is readily metabolized and excreted, the intensity of its action is poor due to these very factors.

To-date, apart from some depigmentation activity noted with corticosteroids at the site of injection, no other group of compounds has been reported to produce marked depigmentation in either animals or humans. In view of the serious drawbacks of the others of hydraquinone and the relatively high systemic metabolism of hydroquinone, safe and effective depigmentation through topical medication heretofore has not been achieved.

It has now been discovered, however, that the p-aminobenzenesulfonic acid compositions hereinafter described may be used topically to produce an effective, reversible depigmentation in highly localized areas. The effectiveness of the compositions of this invention has been confirmed in subjects suffering from hyperpigmentation of various types.

In its composition aspect, the instant invention may be described as residing in the concept of pharmaceutical formulations for topical application comprising, as the essential active ingredient, a member selected from the group consisting of p-aminobenzenesulfonic acid and the alkali metal and alkaline earth metal salts thereof.

In its process aspect, the instant invention may be described as residing in the concept of applying topically a pharmaceutical formulation comprising, as the esential active ingredient, a member selected from the group consisting of p-aminobenzenesulfonic acid and the alkali metal and alkaline earth metal salts thereof in the treatment of hyperpigmentation.

As used herein the term alkali metal and alkaline earth metal includes salts derived from metals such as, for example, lithium, sodium, potassium, rubidium, magnesium, calcium, strontium, barium and the like. The paminobenzenesulfonic acid and its salts as described above are either well-known compounds or may be prepared by methods conventional in the art.

The instant invention is based upon the discovery that p-arninobenzenesulfonic acid and the alkali metal and alkaline earth metal salts thereof, when applied topically to areas of hyperpigmentation, will readily reduce melanin density in the melanocytes of the affected area so that the lesion under treatment assumes the color of the normal skin. The depigmenting agents of this invention may be applied to areas of hyperpigmentation without fear of side effects. Discernible depigmentation of the normal skin surrounding the lesion under treatment is a function of melanin density and may be observed even in individuals displayings normally high pigment density. However with this latter group the effect may be observed only after prolonged treatment.

The depigmenting compositions of this invention can be applied topically in the form of ointments, both hydrophilic and hydrophoblic, in the form of lotions, which may be aqueous, non-aqueous or of the oil-in-water type, or in the form of creams. Pharmaceutical carriers useful in the preparation of such formulations will include, for example, one or a mixture of such substances as water, oils, greases, polyesters, fatty acids, waxes, jellies, etc. Generally, the depigmenting agents of this invention will be present in a minor proportion and the carrier will comprise a major proportion of the pharmaceutical formulation. More particularly, the pharmaceutical formulations contemplated by the present invention include those containing from about 0.1% to saturated solutions, i.e. about 10.0 percent p-aminobenzenesulfonic acid or the alkali metal or alkaline earth metal salt thereof as aqueous or aqueous alcohol solutions or incorporated in a suitable ointment, lotion or cream base. Bacteriostatic agents, exfoliating agents, pigments perfumes, anesthetics may also be incorporated in any of these compositions.

Typical formulations incorporating the depigmenting agents of this invention are described below. These formulations are illustrative merely and no limitation is intended except as set forth in the appended claims.

ANHYDROUS OINTMENT Charge, gm. Stearyl alcohol U.S.P. 30.0 White wax U.S.P. 80.0 White petrolatum U.S.P. 800.0

Formula:

Lanolin, anhydrous U.S.P 40.0 p-Aminobenzenesulfonic acid, anhydrous 50.0 Perfume q.s.

Melt together the stearyl alcohol, white Wax, petrolatum and lanolin at 65 to 70 C. Stir until homogeneous; then cool to 50 C. Add the p-aminobenzenesulfonic acid slowly with agitation to form a smooth dispersion. Mill through a colloid mill at .020 to .030 inch rotor-stator clearance. Add perfume and continue stirring with cooling to 30 C.

p-Aminobenzenesulfonic acid monohydrate 50.0

Sodium hydroxide 10.0 Purified water 590.0

Perfume q.s.

Heat the ingredients of Premix A to 72 C. and stir until uniform. To prepare Premix B, dissolve the sodium hydroxide in the water in a separate container. Add the p-aminobenzenesulfonic acid slowly with stirring until completely dissolved. With continued stirring, add the remaining ingredients. Stir until homogeneous while heating to 75 C. Slowly add Premix B at 75 C. to Premix A at 72 C. Cool with stirring to 45 C. Add perfume and continue stirring and cooling to 30 C.

4 AQUEOUS LOTION Formula: Charge, gm. Sodium hydroxide 11.5

p-Aminobenzencsulfonic acid, monohydrate 55.0 Acrysol A-3 (Rohm and Haas) 850.0 Purified water 90.0

Perfume q.s.

Dissolve the sodium hydroxide in the water. Heat to 60 C. and slowly add the p-aminobenzenesulfonic acid with stirring until completely dissolved. Heat to 60 C. and add the warm solution slowly, with stirring, to the Acrysol A-3. Allow to cool with stirring. At 30 C., add the perfume and continue stirring until homogeneous.

CREAM (SODIUM SALT) Formula: Charge, gm. per kilogram Premix A:

Tegacid Special (Goldschmidt) 150.0 Cetyl alcohol 20.0 Mineral oil U.S.P. 70.0 Stearyl alcohol 30.0 White wax U.S.P. 30.0 Propylene glycol 400 45.0 BRIJ 35 (Atlas Chemical Industries,

Inc.) 25.0 Premix B:

Purified water 552.0 Sodium hydroxide 7.0 p-Aminobenzenesulfonic acid, anhydrous 50.0 Methylparaben 1.2 Perfume 20.0

CREAM (POTASSIUM SALT) Formula: Charge, gm. per kilogram Premix A:

Tegacid Special (Goldschmidt) 150.0 Cetyl alcohol 20.0 Mineral oil U.S.P. 70.0 Stearyl alcohol 30.0 White wax U.S.P 30.0 Propylene glycol 400 45.0 BRIJ 35 (Atlas Chemical Industries,

Inc.) 25.0 Premix B:

Purified water 552.0 Potassium hydroxide 9.8 p-Aminobenzenesulfonic acid, anhydrous 50.0 Methylparaben 1.2 Perfume 20.0

With stirring, heat the ingredients of Premix A to 72 C. and stir until homogeneous. To prepare Premix B, dissolve the alkali (sodium or potassium) hydroxide in the Water in a separate container. Heat to 75 C. With stirring, dissolve the p-aminobenzenesulfonic acid followed by the methylparaben. Add Premix B at 75 C. to Premix A at 72 C. With stirring. Allow the mixture to cool to 40 C. and add perfume. Continue stirring and cooling to 30 C.

Effective depigmentation of hyperpigmented lesions usually requires 1 to 4 daily applications of the topical formulations described above. In severe or aggravated conditions, additional medication may be applied.

The present invention resides in the concept of topical pharmaceutical formulations comprising from about 0.1 to about 10.0 percent by weight of a member selected from the group consisting of p-aminobenzenesulfonic acid and the alkali metal and alkaline earth metal salts thereof. It is contemplated that ointments, creams, lotions or the like which contain the above quantity of active ingredient will be applied daily in the treatment and control of hyperpigmentation.

From a study of the foregoing disclosure, it is, of course, obvious that many compositions containing paminobenzenesulfonic acids other than those specifically illustrated will suggest themselves to those skilled in the art. It will be apparent, for example, that the benzene ring may bear one or more substituents such as lower alkyl, substituted lower alkyl such as haloalkyl and hydroxyalkyl, hydroxy, halogen, especially chlorine and bromine, carbo-lower alkoxy, lower alkoyl, lower alkoxy, nitro and the like. It will also be clear that the amino group and/or the sulfonic acid group may be treated with lower alkanoic acids to form the corresponding N-acylamido and/or sulfonic acid ester derivatives. Further, it will be obvious that solubilizing salts other than the alkali metal and alkaline earth metal salts disclosed above can be formed. Included among these, for example, would be ammonium salts including organic ammonium salts such as salt of mono-, di-, and triethanolamine, ethylamine, di-octylamine, etc. salts. Applicants consider all such compositions to be the full equivalent of the compositions specifically disclosed above and to fall within the scope of the instant invention.

The nature of the vehicle employed is not an essential part of the invention. Various modifications in vehicles will suggest themselves to those skilled in the art and all such modifications fall within the scope of this invention.

The subject matter which applicants regard as their invention is particularly pointed out and distinctly claimed as follows.

We claim:

1. The method for the treatment of hyperpigmentation which comprises the topical application of the hyperpigmented area at least once daily of an effective depigmenting amount of a pharmaceutical formulation comprising from about 0.1 to about 10.0% by weight of a member selected from the group consisting of p-aminobenzenesulfonic acid and the alkali metal and alkaline earth metal salts thereof in a pharmaceutically acceptable carrier for topical application.

2. The method of claim 1 comprising the topical application of p-aminobenzenesulfonic acid.

3.' The method of claim 1 comprising the topical application of the sodium salt of p-aminobenzenesulfonic acid.

4. The method of claim 1 comprising the topical application of the potassium salt of p-aminobenzenesulfonic acid.

5. The method of claim 1 wherein said topical application of said pharmaceutical formulation is made from 1 to 4 times daily.

References Cited UNITED STATES PATENTS 3,086,909 4/ 1963 Otsuki et a1 167-58 FOREIGN PATENTS 113,784- Germany.

OTHER REFERENCES Pivnick et al.: Chem. Abstracts, 1953, vol. 47, p. 11663.

ALBERT T. MEYERS, Primary Examiner D. R. ORE, Assistant Examiner US. Cl. X.R. 424171 

